The RNA-binding protein AKAP8 suppresses tumor metastasis by antagonizing EMT-associated alternative splicing

Hu, Xiaohui; Harvey, Samuel E.; Zheng, Rong; Lyu, Jingyi; Grzeskowiak, Caitlin L.; Powell, Emily; Piwnica‐Worms, Helen; Scott, Kenneth L.; Cheng, Chonghui

doi:10.1038/s41467-020-14304-1

Cited by 86 publications

(89 citation statements)

References 72 publications

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“…For finding events pertaining to EMT, the top 10 000 inclusion and top 10 000 exclusion events were taken into consideration. Out of these top events, those corresponding to genes that are known to get spliced during EMT ( 20 ) were shortlisted. The list of genes that get differentially spliced during EMT (|ΔPSI| ≥ 0.1 and q -value <0.05) were obtained from the RNA sequencing (RNA-seq) data by Hu et al ( 20 ) (GSE139074).…”

Section: Methodsmentioning

confidence: 99%

“…Out of these top events, those corresponding to genes that are known to get spliced during EMT ( 20 ) were shortlisted. The list of genes that get differentially spliced during EMT (|ΔPSI| ≥ 0.1 and q -value <0.05) were obtained from the RNA sequencing (RNA-seq) data by Hu et al ( 20 ) (GSE139074). These genes were shown to have differential splicing in a tamoxifen-inducible HMLE/Twist-ER model of EMT ( Supplementary Table S4 ).…”

Section: Methodsmentioning

confidence: 99%

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Hypoxia-induced TGF-β–RBFOX2–ESRP1 axis regulates human MENA alternative splicing and promotes EMT in breast cancer

et al. 2020

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Hypoxic microenvironment heralds epithelial–mesenchymal transition (EMT), invasion and metastasis in solid tumors. Deregulation of alternative splicing (AS) of several cancer-associated genes has been instrumental in hypoxia-induced EMT. Our study in breast cancer unveils a previously unreported mechanism underlying hypoxia-mediated AS of hMENA, a crucial cytoskeleton remodeler during EMT. We report that the hypoxia-driven depletion of splicing regulator ESRP1 leads to skipping of hMENA exon 11a producing a pro-metastatic isoform, hMENAΔ11a. The transcriptional repression of ESRP1 is mediated by SLUG, which gets stimulated via hypoxia-driven TGF-β signaling. Interestingly, RBFOX2, an otherwise RNA-binding protein, is also found to transcriptionally repress ESRP1 while interacting with SLUG. Similar to SLUG, RBFOX2 gets upregulated under hypoxia via TGF-β signaling. Notably, we found that the exosomal delivery of TGF-β contributes to the elevation of TGF-β signaling under hypoxia. Moreover, our results show that in addition to hMENA, hypoxia-induced TGF-β signaling contributes to global changes in AS of genes associated with EMT. Overall, our findings reveal a new paradigm of hypoxia-driven AS regulation of hMENA and insinuate important implications in therapeutics targeting EMT.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Hypoxia-induced TGF-β–RBFOX2–ESRP1 axis regulates human MENA alternative splicing and promotes EMT in breast cancer

et al. 2020

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“…For example, A-kinase anchor protein 8 is a splicing regulatory factor that suppresses EMT and breast cancer metastasis. 267 In highly metastatic cells, metastasis suppressors are usually downregulated in comparison with primary tumor cells. 265,268,269 In the past decade, a significant number of metastasis suppressors have been identified (Fig.…”

Section: Colonizationmentioning

confidence: 99%

Molecular principles of metastasis: a hallmark of cancer revisited

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Khachfe

et al. 2020

Sig Transduct Target Ther

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Metastasis is the hallmark of cancer that is responsible for the greatest number of cancer-related deaths. Yet, it remains poorly understood. The continuous evolution of cancer biology research and the emergence of new paradigms in the study of metastasis have revealed some of the molecular underpinnings of this dissemination process. The invading tumor cell, on its way to the target site, interacts with other proteins and cells. Recognition of these interactions improved the understanding of some of the biological principles of the metastatic cell that govern its mobility and plasticity. Communication with the tumor microenvironment allows invading cancer cells to overcome stromal challenges, settle, and colonize. These characteristics of cancer cells are driven by genetic and epigenetic modifications within the tumor cell itself and its microenvironment. Establishing the biological mechanisms of the metastatic process is crucial in finding open therapeutic windows for successful interventions. In this review, the authors explore the recent advancements in the field of metastasis and highlight the latest insights that contribute to shaping this hallmark of cancer.

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“…They induce EMT through the transcriptional downregulation of E-cadherin (CDH1) while upregulation of mesenchymal-specific genes of Snail Family Transcriptional Repressor 1/2 (SNAI1/ SNA2), Zinc Finger E-Box Binding Homeobox 1/2 (ZEB1/2), Twist basic helix-loop-helix transcription factor 1/2 (TWIST1/2), Forkhead Box C1/2 (FOXC1/2), Transcription factor 3 (TCF3), Goosecoid Homeobox (GSC) [11]. Additional to these transcription factors, a substantial number of recent studies provided evidence in the involvement of other types of proteins including proto-oncogene Cellular Oncogene Fos (c-FOS), Zinc finger protein 367 (ZNF367), ribosomal protein RPL15, RNA-binding protein A-Kinase Anchor Protein (AKAP8) in regulation of breast cancer metastasis [12][13][14][15][16]. However, for understanding the cellular transition mechanisms lying in the heart of breast cancer metastasis, it is very important to shed light over the epigenetic mechanisms besides these regulations.…”

Section: Introductionmentioning

confidence: 99%

A three layered histone epigenetics in breast cancer metastasis

2020

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Thanks to the advancement in science and technology and a significant number of cancer research programs being carried out throughout the world, the prevention, prognosis and treatment of breast cancer are improving with a positive and steady pace. However, a stern thoughtful attention is required for the metastatic breast cancer casesthe deadliest of all types of breast cancer, with a character of relapse even when treated. In an effort to explore the less travelled avenues, we summarize here studies underlying the aspects of histone epigenetics in breast cancer metastasis. Authoritative reviews on breast cancer epigenetics are already available; however, there is an urgent need to focus on the epigenetics involved in metastatic character of this cancer. Here we put forward a comprehensive review on how different layers of histone epigenetics comprising of histone chaperones, histone variants and histone modifications interplay to create breast cancer metastasis landscape. Finally, we propose a hypothesis of integrating histone-epigenetic factors as biomarkers that encompass different breast cancer subtypes and hence could be exploited as a target of larger population.

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The RNA-binding protein AKAP8 suppresses tumor metastasis by antagonizing EMT-associated alternative splicing

Cited by 86 publications

References 72 publications

Hypoxia-induced TGF-β–RBFOX2–ESRP1 axis regulates human MENA alternative splicing and promotes EMT in breast cancer

Hypoxia-induced TGF-β–RBFOX2–ESRP1 axis regulates human MENA alternative splicing and promotes EMT in breast cancer

Molecular principles of metastasis: a hallmark of cancer revisited

A three layered histone epigenetics in breast cancer metastasis

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